Female Reproductive System and Mammary Gland

CHAPTER 18


Female Reproductive System and Mammary Gland*



The reproductive system is arguably the most important system for the survival of a species. In production animals, reproduction is essential for the continued supply of product, whether it is meat, fiber, milk, or any of the many other by-products. Diseases of the reproductive system have not changed much in the last few decades, but our understanding of many of the processes has progressed dramatically and many of the accepted “dogmas” were challenged and/or modified. In addition, the traditional approach to diseases of the reproductive system focused on specific diseases for which information is known, rather than taking into consideration the overall significance in a clinical setting. In this chapter, each anatomic component or region is examined, and the relative importance of specific diseases or processes is emphasized. The traditional approach also concentrated on bovine and to a lesser extent equine reproductive diseases. In this chapter, diseases of all species, including companion animals, is included in more detail.



Structure



Female Reproductive System


The female reproductive systems of domesticated animals, although diverse in anatomy, share many similarities in structure and function. Embryologic development of the female reproductive tract was thought to be the default when the male reproductive tract did not form, but now we know many unique genes and subsequent processes control it.


Genes initiate the pathways of ovarian differentiation and development. Dax1 is one gene that both promotes ovarian development and inhibits testicular development. In the development of the ovary, the germ cells undergo meiosis and the supporting cells surround the oocytes to become the granulosa and theca cells of the follicles. The differentiation of a female phenotype occurs with the development of the paramesonephric (Müllerian) ducts to form the uterine tube, uterus, and cranial vagina and for the urogenital sinus to develop into the caudal vagina and vulva.


The structural arrangement of the ovary is similar in all species except in the mare. The ovary itself has an outer layer of epithelium, which is of mesothelial origin. The cortex of the ovary contains follicles, stromal connective tissue, and blood vessels. The medulla has large blood vessels, lymphatic vessels, nerves, and loosely arranged connective tissue. Remnants of the mesonephric tubules, called the rete ovarii, are present in this region.


The follicles are where the ova develop and are named according to their stage of development: primordial, primary, secondary, and tertiary types. Each developing follicle has multiple layers of granulosa cells and peripheral theca cells. Ovulation occurs when the follicle ruptures, releasing the ovum and allowing the space to fill with blood and then with luteal cells to form the corpus hemorrhagicum and corpus luteum, respectively. Follicles that do not ovulate become atretic. In addition to these various ovarian structures, cats have interstitial glands that are cells of an endocrine type. The canine ovary has small ingrowths of the ovarian surface that are called subsurface epithelial structures and structures called granulosa cell rests that are aggregates of granulosa cells in a tubular arrangement.


Oogenesis is usually completed by birth. In most species, ovulation occurs through the outer surface of the ovary and the ovum is collected by the infundibulum.


The ovary of the mare differs from the other species in several ways. Equine fetal gonads undergo hypertrophy wherein interstitial endocrine cells, stimulated by equine chorionic gonadotropin (formerly called pregnant mare serum gonadotropin), expand in number and produce an extremely large gonad. These atrophy and disappear before birth. The ovary of the mare has a kidney shape with a depression called the ovulation fossa. The ovum is released from this depression. The follicles in the mare can attain a large size—up to 7 cm. Mares can therefore form a large corpus hemorrhagicum. On occasion, a corpus hemorrhagicum and a corpus luteum can be visible externally as structures that extend outward through the ovulation fossa.


The uterine tube has four regions—the infundibulum, ampulla, isthmus, and uterotubal junction. It is supported by a mesosalpinx. The mesosalpinx of the dog completely surrounds the ovary to form the bursa and has a large amount of fat; a small hole connects the interior aspect to the abdominal cavity. The infundibulum surrounds the ovary of each species, except in the horse where it only covers the ovulation fossa. The uterine tube is where fertilization occurs, and the conceptus then moves into the uterus.


All species have a bicornuate uterus with uterine horns and a uterine body. The uterus of the mare has longitudinal folds. Endometrial cups are present in the endometrium between 37 and 150 days of gestation and are the site of production of equine chorionic gonadotropin, formerly pregnant mare serum gonadotropin (Fig. 18-1). These typically form around the pregnant horn at the bifurcation. Their disappearance is an immune-mediated event. The placenta of the horse is diffuse and microcotyledonary. In ruminants, each uterine horn contains four rows of protuberances that become the caruncles. These may be pigmented in sheep. The placenta of ruminants is cotyledonary. The placenta of the pig is diffuse with small ridges. Dogs and cats have a zonary placenta with marginal hematomas.



The cervix is the structure that separates the external genitalia from the uterus and is an effective barrier from the external environment. Cervical mucus is viscous except during estrus when it becomes more plentiful and thinner. The cervix in the mare, dog, and cat does not have transverse folds as it does in the ruminants and sows. The cervix of the dog and cat opens on the dorsal aspect of the cranial vagina.



Cell Types


In general terms, much of the reproductive system has a barrier between the external environment and the internal environment that is based on epithelium and on an active mucosal immune system. Superimposed on this arrangement are the modifications that occur with the estrous cycle and with pregnancy.


The cell types of the ovary include the epithelium (surface epithelium, subsurface epithelial structures of the bitch, and the rete ovarii), the stroma, germ cells, and follicular cells. Lymphoid cells are usually absent. Control of ovarian function is from the hypothalamus and pituitary through release of gonadotropin-releasing hormone (GnRH), as well as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (see Fig. 12-3).


The uterus is a unique environment that is separated from the external environment by the cervix. Because it is designed to protect and nourish the fetus, there are some unique features of the endometrium. The endometrium has an epithelial lining of columnar and sometimes ciliated cells. There is also a stromal component of the endometrium. Inflammatory and immune cells are present, particularly during estrus, when the uterus is open to the external environment and to spermatozoa or semen (horses and pigs have intrauterine insemination). Mild inflammation is a “normal” part of the estrous cycle, especially in mares after breeding.


The “external” component of the female reproductive tract, which is the vulva, vagina, and part of the cervix, is lined by a stratified squamous epithelium that varies with the stage of cycle. This is best illustrated in the bitch and queen, in which vaginal cytology is a practical guide to determine the stage of cycle. During anestrus, the epithelium is predominantly of a basal type, with a large nucleus and a small amount of cytoplasm. With the progressive approach of estrus (i.e., during proestrus), the epithelium becomes more mature so that at estrus the majority of cells are superficial epithelial cells with either pyknotic nuclei or no nuclei. Lymphoid follicles beneath the epithelium are a normal part of the distal vagina.


Pregnancy brings about a world of change to the reproductive system. The maintenance of pregnancy and the exchange of nutrients between mother and fetus and the exchange of other products from fetus to mother depend on the interactions of the trophoblasts with the endometrium. During pregnancy, the trophoblasts are directly opposed to and in contact with the endometrial epithelium. In cattle, the maintenance of pregnancy depends on the inhibition of prostaglandin F2α (PGF2α) production in the endometrium so luteolysis does not occur. The trophoblast must avoid rejection by the mother and maintain a barrier yet provide a system for the exchange of nutrients and waste products. There is much to be learned about the enigma that is pregnancy.


Some of the cells that we would ordinarily consider “inflammatory” have specific and individual functions separate from their usual roles. Thus uterine macrophages, natural killer cells, and in some cases, neutrophils have separate and distinct functions. For example, macrophages are important in maintaining the size and shape of bovine caruncles, CD2+ T lymphocytes and natural killer–like cells are important in early pregnancy in pigs, and neutrophils are involved in cervical relaxation at parturition in sheep. Thus the usual function of inflammatory cells can be modified or used by the reproductive tract for specific but otherwise unexpected purposes that result in the maintenance of pregnancy.



Mammary Glands



Mammary Development, Lactation, and Involution


The ventrolateral ectoderm of the embryo becomes the mammary ridge and then the mammary complex. In development, mammary buds push into mesenchyme with their number equaling the number of mammae: mares 2, cows 4, ewes and does 2, sows 14, bitches 10, and queens 8. Sprouts form from each mammary bud, and the number equals the number of papillary ducts (and therefore mammary glands) per mamma: mares 2; cows, ewes, and does 1; sows 2; bitches 8 to 14; and queens 3 to 7. Mammae develop in male embryos, but in domesticated species, they only regress fully in the stallion.


As puberty approaches, there is branching of ducts mediated by prolactin, growth hormone, insulin-like growth factors, and many other factors. There is an intimate interaction between the mesenchyme and epithelium in the formation of ducts and alveoli. Mammary development is maximal at the onset of lactation. Milk flows from alveoli through the lactiferous ducts to a lactiferous sinus (in large animals) and with suckling, through the papillary duct or ducts.


There is variation between the species in the amount of regression that occurs when milking ceases. All species reduce the area of secretary epithelium and increase the relative amount of stroma of the gland. When secretion ceases completely, mammary fluid is resorbed. Bovine mammary glands do not regress as much as in other species, and they complete involution in about 2 weeks. Ewes take about 4 weeks to involute. Leukocytes, especially macrophages, infiltrate the involuting gland.



Cell Types


The mammary glands are sequestered from the outside world by the gatekeeper functions of the sphincter of the mammary papilla (teat) and the papillary duct and at least in the ruminant, its lining of keratinized squamous epithelium. The lactiferous sinus and ducts are lined by columnar epithelial cells, and the alveoli have the secretory epithelium. Secretion of milk components occurs in the alveoli. Mammary epithelial cells, specifically the alveolar cells, have receptors for immunoglobulin G (IgG); they are present for about 1 week before parturition, but the receptors disappear during lactation. Epithelial cells also allow for the transfer of IgA, which is produced locally in subepithelial plasma cells, into the alveolar lumens.


Lymphoid cells in the normal glands are derived from blood, and there is also homing of lymphocytes from the intestine (the enteromammary link) as part of the common mucosal immune system. Lymphocytes of the cellular immune system are present also but in low numbers.



Function



Female Reproductive System


The overall function of the female reproductive tract is to provide a location for the conception, development, and eventual release of viable offspring. One offspring is sufficient for dairy cows, but the largest number possible is required for other production animals. Each anatomic site has its own particular function.


The function of the ovary is to develop and release an ovum or ova and to produce hormones, such as estrogen and progesterone, that influence animal behavior and affect other organs and tissue to maintain pregnancy.


The uterine tube acts as a transport system and storage site for spermatozoa. It also collects and transports the ovum or ova and provides a location for fertilization. The conceptus is nourished and eventually transported to the uterus for subsequent development.


The uterus provides a sterile and inert environment for the development of the conceptus. Exchange of nutrients and trophic factors, immunologic components such as immunoglobulin molecules, and waste products is a major function. This is achieved via placental attachment sites that increase the surface area of the interface between maternal and fetal tissue. At the appropriate time, the muscles of the uterus contribute to the release and birth of the developing individual.


The cervix functions as a gatekeeper by holding the products of conception within the uterus until the appointed time. It also provides a seal that prevents organisms and substances from entering the cranial vagina. Its dilation is an important part of parturition.


The vagina and vulva provide a passageway that allows semen to be deposited within an internal site, which protects the spermatozoa from desiccation and excessive contamination with organisms and materials that would excessively irritate or infect the uterus and uterine tube. The vagina also reduces contamination of the cervix, especially during pregnancy. It is also a portal for the fetus at parturition.



Mammary Glands


The mammary glands provide immunity and nutrients to neonates. Milk is the source of many defenses, including antimicrobial, antiinflammatory, and immune-modulating molecules and substances. In the immediate neonatal period, passive transfer of immunoglobulin via colostrum is an important means of providing immediate immunity to offspring of all domestic species. Most domestic species rely on colostrum ingested in the first 24 hours as the sole source of serum immunoglobulin. Dogs and cats are exceptions because there is some transplacental transfer. Components of the cellular immune system, such as lymphocytes and cytokines, are also transferred in milk. After the immediate postnatal period, substances in ingested milk (including immunoglobulin) provide some local protection against intestinal and respiratory pathogens.


The mammary glands of the modern dairy animal are expected to provide much more milk than is necessary for these functions, and the high-producing dairy cow is a special creature, developed to provide a product of good quality with a long shelf-life and modifications to the components of milk to suit consumers. This includes high production with a low somatic cell count.



Responses to Injury



Female Reproductive System


Little is known about the response of the ovary to infection or insults. Observations of neutrophilic and in viral infections, lymphocytic inflammation indicates that the ovary is capable of inflammatory and immune responses as one would expect with other parts of the body. Hyperplasia of the surface epithelium is a common response, just as it is with mesothelium elsewhere.


The uterine tube is such a narrow structure that its function is altered readily with edema, inflammation, and scarring. Exocytosis of neutrophils from blood vessels via the interstitium can be rapid. In sufficient numbers, pus is formed. Local immune responses can develop and result in the presence of lymphocytes, plasma cells, and in some instances, lymphoid follicles. Granulation tissue formation in severe inflammatory conditions leads to scarring, and subsequent obstruction of the tube is followed by an accumulation of fluid (hydrosalpinx) or pus (pyosalpinx).


There are many studies of the response of the uterus to infection. Inflammation varies from mild, in postmating endometritis, to severe, in bacterial metritis and pyometra. In mild acute inflammation of the endometrium (endometritis) of species—apart from the dog and cat—neutrophils and macrophages migrate through the epithelium into the lumen, and the stratum compactum is edematous. This becomes more florid with an increased severity. Neutrophils and necrotic debris accumulate in the uterus until pyometra forms. Lymphocytes and plasma cells accumulate in the stroma of the endometrium. With chronicity and in severe situations, the epithelium becomes squamous, thus squamous metaplasia develops. Necrosis and erosion of the epithelium results in the formation of granulation tissue, and varying degrees of fibrosis are commonplace in severe infectious or inflammatory disease.


The canine endometrium in particular, as well as the feline endometrium, responds with cystic endometrial hyperplasia. Any injury or insult, whether inert foreign material or pathogenic infectious agents, stimulates this response, which occurs in diestrus. The luminal epithelium becomes papillated and can resemble a placental site.


In the vulva and vagina, inflammation and infection of the external part of the reproductive tract results in hyperplasia and keratinization of the stratified squamous epithelium. Exocytosis of inflammatory cells does occur, predominantly with neutrophils. These inflammatory cells do so with some difficulty because of the intercellular junctions between epithelial cells. The inflammatory response is typically lymphocytic and plasmacytic, and these cells can form a thick band of cells beneath the epithelium. Lymphoid follicles often form and give the affected region of the vagina a granular macroscopic appearance.


Reactions of the placenta are stereotyped and rely heavily on the maternal and to a lesser extent, the fetal immune systems. Some species variability is related to the types of placenta and the usual route of infection. The response of the fetus and placenta tends to be relatively rudimentary. Trophoblasts are phagocytic, and they will take up debris, blood, and infectious agents. Reactions of fluid exudation and connective tissue with granulation and fibrosis occur as elsewhere. The reactions of fetal macrophages and neutrophils are less obvious than is seen where maternal leukocytes are readily accessible. Placentitis occurs when there is sufficient time for a response; fetal loss can be rapid with fetal distress, and there can be insufficient time to mount an effective response. Chronic lesions are much more obvious and especially occur in ruminants. The cotyledonary placenta means that attachment of the placenta to the endometrium is restricted to a relatively small area in relation to what may appear to be the total placental area, but the extensive papillation of the components of the placentome produces a very large surface area. The intercotyledonary area is a potential space that can accumulate a large volume of exudate. Chronic inflammation in ruminants is common and identified by fibrosis of the placenta. The neutrophils are probably of maternal origin. Lymphoid follicles and plasma cells are a lesser component of the reaction, but lymphocytes do accumulate beneath the layer of trophoblasts and around blood vessels. In the equine placenta, placentitis involves a small area, usually around the cervical star. There is no potential space because of the diffuse microcotyledonary type of placenta, thus exudates and suppuration are much less prominent; chronic placentitis is rare. The inflammatory reaction in the pig, dog, and cat placenta is mild, and chronic placentitis is rare.



Mammary Glands


The mammary glands are usually sterile but can respond rapidly to infection or other irritants. The responses are stereotyped, however. The columnar epithelial cells can become hyperplastic, but the cells are not able to withstand injury to the same extent as stratified squamous epithelium, thus squamous metaplasia is a frequent occurrence when irritants, such as infection or intramammary preparations, are introduced. Necrosis of the epithelium is common in infectious disease, and granulation and scarring of the lining of the ducts and sinus are frequent.


Although the immune system of the normal mammary glands is quiescent, injury quickly results in recruitment of the various elements. Neutrophils and macrophages are rapidly recruited. Humoral and cellular immunity is typically seen in infectious conditions. The presence of large numbers of plasma cells with the development of a local immune system is an invariable component of the immune response in infection. Edema and subsequent fibrosis are part of the reaction to injury. The flow of milk is often halted by injury and exudates, thus the normal involutionary processes that result in resorption of secretion (macrophage and epithelial uptake) also operate.



Portals Of Entry



Female Reproductive System


It is critical that infectious organisms are excluded from the uterus, otherwise fertility or pregnancy can be jeopardized. Portals of entry are listed in Box 18-1. Organisms that cause inflammation of the uterus can enter through the vulva (ascending infection) or can arrive via the blood (hematogenous infection). Reinfection of the external genitalia from nerves is a unique feature of infection with some herpesviruses.



BOX 18-1   Portals of Entry into the Female Reproductive System, Especially the Uterus




Ascending infections occur at estrus, breeding, and parturition. At estrus, the cervix is open to admit spermatozoa. Contamination of the cranial vagina is very important in determining whether infection of the uterus occurs or not. Conformational and structural changes in the vulva and vagina are also important determinants of infection. These are discussed in more detail later. A subcategory of ascending infection is infection of semen by infectious agents. There are many agents, including bacteria, viruses, protozoa, and Ureaplasma and Mycoplasma spp., which can be acquired in this fashion. These are discussed further in the discussion on disorders of the uterus in the section on disorders of the Female Reproductive System. Ascending infection is the major portal by which the equine placenta becomes infected with bacteria or fungi. The cervix in the mare is “loose,” attains a much larger diameter, and can be readily opened with digital pressure. It is virtually impossible to penetrate the cervix of other species with a probe without creating severe trauma. Infection of the uterus and/or placenta by the ascending route with Streptococcus zooepidemicus is common in the mare, but most ascending infections in other species include a mixture of bacteria. This is particularly the case with postpartum infection.


Hematogenous infections are less common and are usually involved in specific infections, such as in brucellosis, salmonellosis, pestivirus, and herpesvirus infections, and they usually occur during pregnancy. Many of the fungal infections of the placenta occur via the hematogenous route.


There are some instances in which infections appear to descend from the ovary through the uterine tube. Some viral, chlamydial, and Ureaplasma infections can be descending.


Transaxonal infection of the distal reproductive tract occurs with some herpesviruses, where stressful events, such as parturition, cause a recrudescence. Neonates can be exposed and infected via this route, but clinical disease in the mother is unusual.



Mammary Glands


Portals of entry are listed in Box 18-2. Most infectious agents and foreign material (intramammary preparations) enter the gland in an ascending fashion via the papillary duct. Small (bacteria) and large (leaches) pathogens can enter the gland via this route. There are some instances in which organisms home to the mammary glands from systemic infection, but their number is small. Viruses, such as the retroviruses of caprine arthritis and encephalitis, ovine maedi-visna, and Mycoplasma spp., are good examples. Penetrating injury is rare.



BOX 18-2   Portals of Entry into the Mammary Glands





Defense Mechanisms



Female Reproductive System


Innate, nonimmune, or physical factors are very important in the defense of the reproductive system. An adaptive immune system occurs after these have failed. In many instances, failure of the physical factors that result in infection of the tract is too late for the fetus, and infertility and failure of pregnancy occurs. Defense mechanisms are listed in Box 18-3.



BOX 18-3   Defenses of the Female Reproductive System





Innate Immunity


The reproductive tract requires a defense system that provides a sterile environment for the fetus but allows entry of antigenic and infectious materials (semen). It does this by providing specialized epithelium in the “contaminated” environment of the vulva and vagina, and then has a specialized structure, the cervix, to exclude most agents from the upper “sterile” regions. Vaginal epithelium has intercellular tight junctions that inhibit the transepithelial migration of agents and molecules, and it has molecules that detect pathogen-associated molecular patterns. These pattern recognition receptors, including Toll-like receptors and defensins, exclude or direct actions against many pathogens.


The anatomy and integrity of the cervix is very important in the exclusion of infectious agents from the uterus. Contamination of the cranial vagina is an additional factor, and conformation of the external genitalia is the physical factor that has received the most attention in relation to uterine infections. In older multiparous mares, the vulva is frequently higher than the floor of the pelvic canal and tends to become horizontal; air and contaminants, including feces, are sucked in or allowed entry into the vagina or even into the uterus. Urine can pool in the vagina of mares with defective function of the vestibule and vulval muscles. When contamination and pooling of urine occur, the vestibule and vagina become inflamed. Subsequently, the cervix and uterus also become affected, either from direct contact with environmental organisms or from local spread of the inflammation.


Muscular contractions of the uterus and gravitational drainage of secretions (mucus, lochia) from the uterus and vagina are physical factors that can flush out infectious organisms. Congenital malformations and anomalies, such as persistent hymen, can reduce outflow and increase pooling in the vagina and uterus. The altered environment of the vagina in spayed, obese bitches can predispose the vagina and vulva to infection.


After infection or irritation from semen, changes include hyperemia and edema of the uterine wall and lumen. These have the theoretical effect of diluting infectious or irritant substances. Recruitment of neutrophils from the blood occurs in response to chemotactic substances released by bacteria, complement, and inflammatory mediators from endometrium and leukocytes. Attracted neutrophils infiltrate the endometrium, enter the uterine lumen, and contribute additional amounts of inflammatory mediators, providing additional chemotactic stimuli. Complement activation, directly by bacteria via the alternate pathway or by specific antibody via the classical pathway, can eliminate bacteria, either by lysis after attack on their membranes or by phagocytosis enhanced by opsonization.



Adaptive Immunity


The reproductive tract is a unique environment because it must respond adequately to challenge from pathogens, yet tolerate the allogeneic spermatozoa and fetus. Adaptive immune responses, whether humoral or cellular, have to be carefully controlled. Control is achieved by differing cytokine expression of epithelial cells and their effects on regulatory T lymphocytes that make “decisions” as to the type and extent of the response. There is likely to be variation in the response, depending on the location. The response in the “sterile” compartments of the uterus and uterine tube are different from that of the “nonsterile” vagina and ectocervix.


Although the upper reproductive tract is part of the common mucosal immune system, it differs from intestinal and bronchial tissues because it does not have mucosal-associated lymphoid tissue (MALT) analogous to Peyer’s patches. This difference occurs because of the lack of continuous antigenic stimulation. Lymphoid follicles, however, are present in the vulva and distal vagina. The uterus also has the added potential influence of hormones to modify responses.


T lymphocytes are critical in determining whether the appropriate response is predominantly humoral or cell mediated. CD8+ T lymphocytes are the most common lymphocytes of the luminal endometrial epithelium and stroma (stratum compactum especially), although there is variation, depending on the location in the uterus. For example, CD4+ lymphocytes are more common in the horns of the uterus of mares, whereas CD8+ lymphocytes are more numerous in the body.


Little is known of the T lymphocyte and cell-mediated immune system of the reproductive tract; much more is known about its humoral immune system. It is generally believed that locally produced antibodies are more important in those diseases that are acquired by ascending infection, for example, Tritrichomonas foetus in cattle, whereas systemic immunity is more important in systemically or hematogenously acquired infections, such as Brucella sp. infection. The immunoglobulin isotype (IgA or IgG) and subisotype (IgG1 or IgG2) that is found in an individual infection is unique to that infection. The generalization that IgA is the main mucosal antibody is not always the case. The response to specific infectious agents is not uniform, and there are differing responses between species. Protection against Tritrichomonas foetus in cattle, for example, is mostly by IgG1. Local transfer of immunoglobulin occurs at all levels of the tract.


Leakage of serum into the uterine lumen from an inflamed endometrium also contributes to the antibody content of the uterine fluid. Opsonization of bacteria by antibodies, especially IgG, promotes more efficient phagocytosis by neutrophils and macrophages; thus they enhance the innate cellular response by phagocytes.


The influence of the estrous cycle on antibodies in the uterus is controversial, but data suggest that concentrations of luminal immunoglobulins and immunoglobulin-containing cells in the endometrium are not influenced by the stage of the estrous cycle.


Locally produced IgA interferes with attachment of bacteria to mucosal surfaces and can activate complement via the alternate pathway. It is not directly bactericidal and acts neither as an opsonin nor as a macrophage activator. Variations occur among species on the position in the tract where the concentration of IgA is greatest, but the sites correspond to the site of semen deposition (uterus in mares, vagina in cows).



Hormonal Influences on Innate and Adaptive Immunity


Infections of the uterus are more easily overcome at estrus than at other stages of the cycle. This increased response at estrus is probably a result at least in part to better drainage through an open cervix. Both estrogen and progesterone affect neutrophil and lymphocyte function, but there is variation in results obtained when the effects of hormones were studied. In some species, such as the mouse, estrogen induces an influx of neutrophils and macrophages (at estrus). Estrogen can also be involved in the upregulation of subsets of T lymphocytes. There is variation in the numbers of lymphocytes in the reproductive tract during the estrous cycle. Even so, there is evidence that CD4+ lymphocytes increase in number with increases in estrogen concentration. Progesterone, which dominates during the luteal phase and pregnancy, antagonizes the “proinflammatory” activity of estrogen. Studies in cattle and sheep indicate an upregulation of T and B lymphocyte responses during the follicular phase of the estrous cycle when estrogen dominates. Major histocompatibility complex II (MHC II) expression is enhanced at estrus in direct relationship with rising estrogen concentration. The influence of the estrous cycle on antibodies in the uterus is controversial, but data suggest that concentrations of luminal immunoglobulins and immunoglobulin-containing cells in the endometrium are not influenced by the stage of the estrous cycle. Generally, the uterus is more susceptible to infection during the progestational or luteal phase of the estrous cycle and during pregnancy. The nonpregnant uterus is highly resistant to infection. The mechanisms involved in the effect of sex hormones on neutrophils are unknown, and receptors for sex hormones have not been demonstrated in them.


Prostaglandins are normally produced by the epithelium of the endometrium. In most species (excluding the dog, cat, and primates), prostaglandins are responsible for lysis of the corpus luteum. In acute inflammation, prostaglandin production by the endometrium is increased, and lysis of the corpus luteum occurs. When there is epithelial and mucosal surface loss, production of prostaglandins is decreased, the corpus luteum persists, and the more susceptible progestational uterine environment is maintained.



Mammary Glands


As with the body in general, the mammary glands have a full range of mechanisms to prevent and control infectious disease. It relies heavily on isolation. The structure and function of the papillary duct of the teat and the keratin that accumulates there to form a plug prevent many potential pathogens from entering the gland. Secretions of the gland contain antimicrobial, antiinflammatory, and immune-modulating substances. Within the gland, there also are humoral and cellular defenses. Innate defense mechanisms are listed in Box 18-4.



BOX 18-4   Innate or Nonspecific Defenses of the Mammary Glands





Innate Immunity


Physical factors are very important in the resistance to infection. The teat orifice, with its sphincter, and the papillary duct offer mechanical resistance to the entry of organisms. The keratin and waxy nature of the inner aspect of the papillary duct can be protective by having bactericidal fatty acids, by adsorbing bacteria and desquamating when coated with bacteria, and by desiccating. Delays in the formation of the keratin plug at drying off or cracks in the teat ends increase the risk of intramammary infection. Regular milking of the lactating mammary glands probably is a natural defense mechanism because of the flushing of organisms and products of inflammation from the gland.


Soluble factors are numerous and contribute to resistance to infection. Lactoferrin, the major iron-binding protein of saliva and milk, is a nonspecific natural protective factor in milk. Mammary epithelial cells produce the bulk of lactoferrin in milk. Lactoferrin concentration is increased in acute mastitis and in the involuting gland. The binding of iron withholds this essential nutrient from pathogenic bacteria and thus has a bacteriostatic effect. The lactoperoxidase-thiocyanate-H2O2 system temporarily inhibits some streptococci and coliforms and Staphylococcus aureus. Lactoperoxidase is synthesized by mammary epithelium, thiocyanate is derived from certain green feeds, and H2O2 is produced by enzymic constituents of milk by streptococci or from an exogenous source. Hypothiocyanite produced by the lactoperoxidase system damages the inner bacterial membrane, killing the bacteria. Lysozyme, synthesized locally or from blood, destroys bacteria by lysis of cell wall peptidoglycan. Complement activated in mastitis by the alternate pathway in response to the presence of bacterial endotoxin can be important in bactericidal activity, opsonization, and promoting inflammation. Normal milk is antiinflammatory. Cytokines have a broad range of immunomodulation. Molecules of this general group include the interleukins (IL-2, especially), colony-stimulating factors (CSF), interferons (IFN), and tumor necrosis factor (TNF).


Cells that are not part of the adaptive or acquired immune system include macrophages, neutrophils, and natural killer cells. Macrophages are usually the most numerous leukocyte in mammary secretions. They phagocytose bacteria and act as antigen-presenting cells. Macrophages can be found free in the alveoli and the interstitium, as well as in the lamina propria of the lactiferous sinus and interlobular and intralobular lactiferous ducts. In a lactating cow, at least 500,000 phagocytes per milliliter of milk are necessary for defense of the mammary glands against invading bacteria. In uninfected bovine mammary glands, 50,000 to 200,000 neutrophils and macrophages per milliliter of milk are present, with the macrophages predominating. Lymphocytes represent about 10% of the leukocytes in lactation. Neutrophils are present only in low numbers unless there is bacterial infection or injury, when their influx can be dramatic. Neutrophils play an extremely important role in antibacterial action by phagocytosis and the release of antibacterial substances. Their function is inhibited in the periparturient period. Recruitment can be so rapid that neutrophils are the dominant cells as soon as 2 hours after infection. Cell counts in milk can average 700,000 per milliliter in subclinically infected quarters, and millions of neutrophils per milliliter are common in clinical infections.


Although neutrophils recruited from the blood are important in fighting infection in the mammary glands, they do not kill bacteria as well in milk as they do in blood. Milk seems to be a poor medium for the functioning of neutrophils. Some possible reasons include the absence of glucose in milk for the glycolytic metabolism of neutrophils, decreased amounts of glycogen in milk neutrophils, deficiency of opsonins and complement in milk, coating of the surface of neutrophils with casein, loss of neutrophil pseudopodia caused by phagocytosis of fat, and a decrease of hydrolytic enzymes within neutrophils after phagocytosis of casein and fat.


In experimental staphylococcal mastitis, the numbers of inflammatory cells (mostly neutrophils) in milk cycle up and down every several days, with a corresponding inverse cycling of the number of viable bacteria. When cell counts are at a peak, phagocytosis is optimal and bactericidal activity per cell is most efficient, by as much as 10,000-fold higher. The frequency and periodicity of the cycle, as well as the amplitude of the cell and bacterial counts, are independent for each infected quarter. The likely source of reinfection of the mammary glands is neutrophils that are inefficient at killing phagocytosed bacteria at the time of low cell count. As these cells undergo necrosis and lysis, their previously protected intracellular viable bacteria are released to multiply, and the inverse cycling of neutrophils and bacterial numbers continues.


In the first week after parturition, when neutrophils are most needed to deal with mammary infections, bovine blood neutrophils already are defective before they pass into the mammary glands. They have significantly impaired chemokinesis and decreased superoxide anion production, antibody-dependent cell-mediated cytotoxicity, and phagocytosis of bacteria. The causes are probably some combination of the effects of stress, energy, and protein demands of early lactation and the hormonal fluxes of this stage of the reproductive cycle. In the parturient period, the concentration of glucocorticoids is increased. This means that leukocyte function is less effective, because expression of l-selectin and CD18 on neutrophils are downregulated by glucocorticoids. This downregulates adhesion between neutrophils and vascular endothelium and transendothelial migration of neutrophils. Neutrophils are also important in creating bystander injury when the products of neutrophil granules, such as superoxide anions and enzymes, are released during phagocytosis and with neutrophil destruction.


Natural killer cells use perforin to kill bacteria in a major histocompatibility complex (MHC) independent way and is part of the nonspecific defenses of the gland.



Adaptive Immunity


The humoral immune system operates in the mammary glands in several ways apart from the transfer of immunoglobulin in colostrum and during lactation. Antibody concentration in normal bovine milk is small, about 1 mg/mL, and includes IgA, IgM, IgG1, and IgG2. IgA and IgM are synthesized locally in the stromal tissue of the acini of the mammary glands and may be part of the enteromammary link of the mucosal immune system, whereby lymphocytes from gut-associated lymphoid tissue (GALT) home to the gland. Most IgG is serum derived; IgG1 is selectively transferred into mammary secretion and is the major immunoglobulin class in milk obtained from healthy mammary glands. IgG2 is both serum derived and locally produced by resident plasma cells, especially in inflammation.


Particulate antigens, such as bacteria, stimulate an antibody response in the mammary glands of the cow, whereas soluble antigens do not. In colostrum and in milk from inflamed mammary glands, antibody concentration approaches 50 mg/mL. Early in inflammation, IgG1 and IgG2 opsonize bacteria to enhance phagocytosis by macrophages, but later the importance of IgG2 as an opsonin increases as neutrophils enter the gland. Neutrophils can transport IgG2 to the mammary glands as they move to the site of inflammation. IgM also functions as an opsonin. IgA does not opsonize but could prevent bacterial adherence to epithelium, inhibit bacterial multiplication, neutralize leukocyte-inhibiting bacterial toxins, and agglutinate bacteria. Concentrations of immunoglobulin are reduced in the periparturient period and may contribute to the increased susceptibility of the gland to infection.


Cell-mediated immunity in the gland is stimulated in infectious disease. Interleukins from mammary macrophages stimulate the immune system by activating T and B lymphocytes. Only a few B lymphocytes are present in the normal mammary glands and milk. T lymphocytes in normal mammary tissue and milk of cows and pigs are mostly CD8+ α/β T lymphocytes. The CD4+/CD8+ ratio is <1, which is reversed from the ratio in blood. The mammary glands thus have selective lymphocyte trafficking, favoring CD8+ lymphocytes, which have either cytotoxic or suppressor function. T lymphocytes that activate B lymphocytes, T lymphocytes, and macrophages are underrepresented in normal mammary tissue and milk. CD8+ T lymphocytes are found in the lactiferous duct and alveolar epithelium, whereas the lesser numbers of CD4+ lymphocytes and B lymphocytes are in clusters in the connective tissues. In early lactation, the CD8+ lymphocytes in milk function more as suppressor lymphocytes than cytotoxic lymphocytes, but the situation is reversed in mid and late lactation. Suppressor T lymphocytes control, modulate, or suppress the immune response, and cytotoxic T lymphocytes can act as scavengers, removing damaged mammary cells. CD4+ (T helper [TH]) lymphocytes predominate in goat mammary glands and in mastitis. In response to bacterial infection, an influx of CD4+ T lymphocytes occurs in milk, and these lymphocytes eventually outnumber CD8+ T lymphocytes. During the periparturient period, TH2 lymphocytes (cell-mediated response) secreting IL-4 and IL-10 predominate over TH1 lymphocytes (humoral-mediated response) secreting IL-2 and INF-γ. T lymphocytes may be cytotoxic, and they preferentially migrate to epithelial surfaces and can destroy altered epithelial cells. γ/δ T lymphocytes are present in greater numbers in mammary secretions and parenchyma when compared with blood. The percentage of γ/δ T lymphocytes of mammary parenchymal lymphocytes decreases in the postpartum period, a time of increased susceptibility of the mammary glands to disease, which suggests that γ/δ T lymphocytes can be important in defense against infection.



Disorders Of Domestic Animals (Horses, Ruminants [Cattle, Sheep, And Goats], Pigs, Dogs, And Cats)



Female Reproductive System



Disorders of Sexual Development


An understanding of the development of the reproductive tract of domesticated animals is from studies in multiple species, including humans, laboratory rodents, and pigs. Sequencing of the genomes of animals now makes identification of genes and processes responsible for sexual development easier. Developmental anomalies and neoplasia are better understood, too. There is a pragmatic reason for examining embryology: it is easier to learn the mechanisms of how anomalies occur and to determine their significance rather than memorize every possible disorder.



Normal Sexual Development: Sexual development occurs in three sequential processes: (1) chromosomal sex is established at conception, (2) gonadal sex occurs early in fetal development, and (3) phenotypic sex soon follows. Germ cells migrate from the yolk sac to the genital ridge, and without germ cells the ovaries do not develop, and dysgenesis is the result. The undifferentiated and bipotential gonad acquires germ cells, mesenchymal cells, coelomic epithelial cells, and mesonephric epithelial cells. These form the major cell types in the developed gonad: germ cells; supporting, steroid-producing cells and unspecialized mesenchyme; and epithelium. Before differentiation into male and female, the embryo has a double set of ducts: the mesonephric (Wolffian) ducts and tubules and the paramesonephric (Müllerian) duct (Fig. 18-2). In individuals with a chromosomal sex of XX (female), without the sex-determining region of the Y chromosome (SRY negative), there is activation of genes and gene products so that a normal ovary develops. Development of a testis is inhibited. The tubular genitalia of the female develop from the paramesonephric ducts, and the mesonephric ducts disappear. The paramesonephric ducts are paired and join the urogenital sinus. They fuse to form the cranial vagina and the uterine body. The urogenital sinus forms the vulva and posterior part of the vagina. The external genital tubercle forms the clitoris. All stages of the development of the genitalia are under the control of genes and gene products; the female reproductive system is not a “default” system.




Major Anomalies: Major anomalies are those that result in dramatic abnormalities in sexual phenotype and usually result in infertility. Affected animals are phenotypically male, female, or ambiguous or altered. The exact defect cannot be reliably determined from phenotypic characteristics alone. There are a large number of individual steps involved in sexual development and differentiation, and missing or changing one step can have major effects on subsequent differentiation. Common disorders of sexual development (DSD) are listed in Table 18-1.



Abnormal location and size of the external genitalia creating phenotypic ambiguity is often an indication of a major underlying anomaly. A basic definition of syndromes and identifying the underlying defect and pathogenesis requires an assessment of the sex chromosomes, presence or absence of genes like SRY, gonadal type, and phenotype.


Sex chromosome DSD are those with an abnormal number and/or mixture of sex chromosomes, including XXY (Klinefelter syndrome), X_ (Turner syndrome), and XX/XY (chimerism). XY disorders of sexual development are those with disorders of testicular development, disorders of androgen synthesis or action, and miscellaneous conditions (see Chapter 19). XX DSD includes disorders of ovarian development, androgen excess, or miscellaneous disorders. The greater availability of tests for the SRY gene means a greater ability to define the underlying anomaly. XX disorders are now defined as XX SRY positive and XX SRY negative, and XY disorders are subdivided into XY SRY-positive and XY SRY-negative genotypes.


Gonadal anomalies are found at surgery or necropsy. Histologic assessment is necessary to differentiate between rudimentary gonads (gonadal dysgenesis), testis, ovary, and ovotestis or a combination of both male and female gonadal structures in a single gonad. In phenotypic females, the lack of an estrous cycle, an enlarged clitoris, and/or an increased distance from the anus to vulva may indicate an abnormality. Sex reversal, hermaphroditism, pseudohermaphroditism, and feminization are examples of clinical terms used to describe an abnormality. Descriptions of the phenotypic and gonadal anomalies are often done without the benefit of genotype, but it is preferable to describe the disorder completely as outlined next.



Sex Chromosome Disorders of Sexual Development: True chromosomal DSD is very rare. Cases of X_ (Turner syndrome) and XXY (Klinefelter syndrome) are reported. They usually have gonadal dysgenesis and a feminine phenotype.


Chimerism is more common. Chimeras and mosaics have two or more somatic cell types, each with a different chromosomal constitution. Chimeras have two genetically distinct cell types that come from different individuals, whereas mosaicism is a different chromosomal constitution from altered mitosis. The most common chimera in domestic animals is the freemartin calf (Fig. 18-3). Vessels of the placentas from two different fetuses fuse and exchange blood between fetuses. Each fetus becomes a hematopoietic chimera. Anastomosis of placental vessels occurs most often in bovine species and less frequently in other ruminants and pigs. The freemartin is the female of a set of male and female twins. Gene products from the cells of the male fetus induce fetal Sertoli cells and seminiferous cordlike structures in the ovaries of the female twin. The ovaries are small and can have reduced number of or no germ cells or organs partially converted to testes. The paramesonephric (Müllerian) duct derivatives vary from almost normal to cordlike structures, but their lumens do not communication with the vagina. The vagina, vestibule, and vulva are hypoplastic. Vesicular glands are always present; other mesonephric (Wolffian) structures are present to varying degrees. Externally, the animal has a female phenotype, but the vestibule and vagina are short, the vulva is hypoplastic, and the clitoris is enlarged. The male twin is minimally affected.




XY Disorders of Sexual Development: XY DSD has a normal male chromosomal component (XY) and a female phenotype. They have abnormal gonadal development that drives phenotypic abnormalities, abnormal androgen synthesis, or lack androgen receptors. They are described according to the presence or absence of the SRY gene and the gonadal type. The most extreme example is XY DSD, SRY-positive with testes and female phenotype. These were called male pseudohermaphrodites, testicular feminization, or XY sex reversal (Fig. 18-4). They usually lack androgen receptors. Serum testosterone is present, but the genitalia are female. A mild form occurs in Miniature schnauzers with persistent Müllerian duct syndrome. They are XY males with a complete paramesonephric system, including uterine tube, uterus, and cranial portion of the vagina. They lack the anti-Müllerian hormone (AMH, previously called Müllerian inhibitory substance) or its receptor. XY DSD, SRY negative with gonadal dysgenesis and female phenotype is another category and is found in horses and other species. They have hypoplastic or undifferentiated gonads and a female phenotype.




XX Disorders of Sexual Development: The only category of XX DSD reported in animals is XX DSD, SRY negative. Most are XX DSD, SRY negative with ovotestes and a female but ambiguous phenotype. They are usually true hermaphrodites with both male and female gonads (Fig. 18-5). They are phenotypically female, with masculinization, for example, an enlarged clitoris. American cocker spaniels and some other breeds of dog have this autosomal recessive trait. In goats, it is associated with the polled gene. Confirmation of this syndrome requires genotyping because in the case of goats, the presence of mammary development in bucks is not always an indication of an XX DSD.




Anomalies with Normal Sexual Development: There are many different anomalies found in individuals with normal genotypic, gonadal, and phenotypic sex. They include failure of the normal maturation, hypoplasia, or aplasia of parts of the internal or external genitalia. Because normal development requires such intricate timing of events, including regression of some parts, the joining of tubes and tubules, migration of components from one site to another, the interaction of genes, and hormones and local factors, it is no wonder there are myriad anomalies.


Segmental aplasia of the paramesonephric duct can affect any part and little is known of its pathogenesis. A genetic basis is implicated in shorthorn cattle, in which it is linked to the recessive gene for white coat color. The simplest form is failure of the paramesonephric duct to make a proper connection with the urogenital sinus, leaving a persistent hymen, a membrane at the site where the two precursor tissues join (Fig. 18-6). A perforated hymen sometimes persists and is not clinically significant. If the hymen is complete and there is no drainage of fluid from the uterus, the upstream portion of the vagina, cervix, and uterus distend with normal secretions. In the more severe forms of segmental aplasia, one or more segments of the vagina, cervix, uterine body, and uterine horns are absent or rudimentary. Aplasia of a segment of the uterus (Fig. 18-7) occurs in cattle. Prostaglandin can be synthesized and released from the blind ending uterine horn, just as is produced by a normally connected uterine horn. In those with a local utero-ovarian pathway for luteolysis, such as the cow, the absence of a segment of the uterus could result in insufficient PGF2α to cause regression of the corpus luteum. In the pig, where systemic transmission of PGF2α from the endometrium to the corpus luteum is important, prostaglandins from the blind uterine horn can have a lytic effect on the corpora lutea of pregnancy in the contralateral ovary. In the dog and cat, the uterus does not play a role in the regression of the corpus luteum.




Imperfect lateral fusion of the paired paramesonephric ducts results in anomalies. Normally the two ducts unite first at the cloacal end to form the vagina. The fusion moves cranially to form the cervix and the uterine body. Malformations caused by imperfect fusion are most common in and adjacent to the cervix. They range from a dorsoventral fibrous band in the cranial vagina, failure of fusion of the caudal cervix with bifurcation of the cervical canal, to complete duplication of the cervix and body of the uterus (uterus didelphys).


Hypoplasia (and its extreme, aplasia) of a portion of the reproductive tract apart from the tubular genitalia comes in many different degrees. Gonadal hypoplasia is common, especially in males, and these are discussed in the relevant sections.



Minor Anomalies: Minor or incidental anomalies are myriad in the reproductive tract. The same factors influencing the development of major anomalies in animals with normal sexual differentiation also operate here. Minor anomalies are incidental and not clinically significant apart from potentially being mistaken for lesions that do cause infertility, subfertility, or are life threatening. Foremost of these are the numerous cysts and tubular remnants. Periovarian cysts are extremely common and can be confused with cystic neoplasms. They can be derived from paramesonephric ducts, mesonephric ducts, and mesonephric tubules. Web Table 18-1 lists the location and names of common incidental cystic anomalies. They are discussed in more detail later.




Inclusion cysts of the reproductive tract are isolated cysts not derived from embryonic elements. The serosal inclusion cyst of the uterus in bitches is a common type (Fig. 18-8). It arises from a small group of mesothelial cells trapped beneath the serosal surface during involution of the uterus. These grapelike clusters of semitransparent thin-walled cysts are located on the serosal surface of the uterus. Subsequent distention and enlargement result in numerous cysts developing.




Common Syndromes


Many of the commonly seen syndromes of sexual development are listed in Table 18-1.



Ovary:



Developmental Anomalies: Agenesis, a total lack of ovarian tissue, can involve one or both ovaries. The entire reproductive tract also can be absent. In cases of bilateral agenesis, the tubular genitalia remain infantile.


Duplication of an ovary is a rare anomaly that arises by two different mechanisms: originating separately or splitting of an already developing ovary. The latter type is close to the normally located organ and may be connected to it. This anomaly is an uncommon cause of ovarian remnant syndrome, in which previously but incompletely spayed cats and dogs come into heat (estrus) again.


Hypoplasia of the ovaries occurs most commonly in cows. It occurs in Swedish Highland cattle as an autosomal recessive trait with incomplete penetrance. It is either unilateral or bilateral. The number of primordial follicles and the proportion of Graafian follicles are fewer than normal. Ovarian hypoplasia occurs with chromosomal DSD such as XXX and X_ chromosomes in mares and XXX DSD in cows. It is usually bilateral but not symmetric. The affected ovaries are small and lack follicles or surface scars from ovulation. Microscopically, cortical stroma and ova are absent or poorly developed. The tubular genitalia remain infantile after the expected time of puberty. Other causes of an infantile reproductive tract are malnutrition or other forms of debility. Ovaries in these animals, however, have numerous primordial follicles and can respond to gonadotropic hormones after removal of the debilitating factor.


Vascular hamartomas of the ovary are incidental findings in the mare, cow, and sow. They appear as a dark red mass on the surface of the ovary and consist of connective tissue and vascular channels lined by mature endothelial cells.



Cysts In and Around the Ovary: Periovarian (paraovarian) cysts are cysts that are external to the ovary. They are common findings in dogs and cats during ovariohysterectomy (see Web Table 18-1). Intraovarian cysts are the cysts within the ovary. These should be differentiated from cystic neoplasms (see next section).



Periovarian cysts: Periovarian cysts are usually cystic remnants of embryonic structures, either paramesonephric ducts or mesonephric tubules or ducts. Location of the cyst helps differentiate them. Cystic remnants of the paramesonephric ducts include the fimbrial cyst and the cystic accessory uterine tube. This is common in the mare and called the hydatid of Morgagni (Fig. 18-9). Hydatid of Morgagni measure up to several centimeters in diameter and are cranial to the ovary in the mesovarium. Cystic accessory uterine tubes are in the mesosalphynx. Histologically, they resemble the normal uterus and have a thin coat of muscle. There are cysts that arise from mesonephric remnants, either ducts or tubules. Cysts of the mesonephric duct are in the cranial or caudal mesovarium and histologically have a thick smooth muscle coat.




Intraovarian cysts: Intraovarian cysts are numerous and common. Many are derived from Graafian follicles but others are epithelial cysts from the surface epithelium or from the intraovarian rete ovarii, embryonic structures of mesonephric tubular origin. The most common in the mare is an epithelial inclusion cyst, and the most common in the dog and cat is the cystic rete ovarii (Fig. 18-10).



Epithelial inclusion cysts in mares can cause infertility (see Web Table 18-1). They are located in the ovary around the ovulation fossa. Epithelium from the surface of the ovary becomes pinched off and embedded in the stroma during ovulation. This epithelium produces fluid that causes the structure to enlarge and eventually reach several centimeters in diameter. They are identical in appearance to large follicles, but they do not appear and disappear as follicles should; histologic assessment is necessary for diagnosis. Their size and number may block ovulation. Epithelial inclusion cysts in other species, or cysts of subsurface epithelial structures in bitches form in a similar manner, but they are in the capsule of the ovary and are small and incidental.


Cystic ovarian (Graafian) follicles, or follicular cysts, are defined as follicles that are larger than normal. They are especially important in cows and sows. The disease in cows is called cystic ovarian degeneration (COD). Bovine cystic follicles are 2.5 cm or more in diameter (Fig. 18-11) and persist for 10 or more days without the formation of a corpus luteum. The prolongation of the postpartum interval to first estrus (so called days-open) is the main consequence of cystic follicles. Ovulation does not occur. These cysts probably develop because of an abnormality of the hypothalamo-hypophyseal-ovarian axis that causes a deficiency of LH or of the LH receptor in the ovary, although the mechanism is not confirmed. Cystic ovarian degeneration is treated with GnRH, which causes release of LH in the pituitary, and with chorionic gonadotropin (high in LH). Evidence suggests that stress is involved wherein adrenocorticotropic hormone (ACTH) or cortisol inhibits GnRH release from the hypothalamus and prevents upregulation of LH receptors in the ovary. Higher concentrations of progesterone can have a similar effect. The end result is an inadequate LH surge and failure of ovulation. In a similar way, postpartum uterine infection can cause cystic follicles. Escherichia coli infection of the uterus increases concentrations of serum PGF2α metabolites and cortisol. It was proposed that bacterial endotoxins, or the prostaglandins produced because of damage caused by endotoxins, stimulate the adrenal cortical secretion of cortisol; cortisol excess suppresses the preovulatory release of LH, resulting in the development of cysts.



Luteinized cysts are anovulatory luteinized follicular cysts. They develop from follicular cysts by delayed or insufficient release of LH and are therefore part of COD (see Web Table 18-1). It therefore occurs in cows and sows more often than in other species. Luteinized cells line the cystic cavity. Cystic follicles and luteinized cysts can occur in the same ovary.


Cystic corpus luteum is a corpus luteum with a cystic center. It is unknown why a follicle fails to luteinize fully. The cystic center is larger than the normal small central cavity that occurs normally in some corpora lutea. Ovulation occurs in a normal follicle, but a large irregular cystic center develops (Fig. 18-12). The length of the estrous cycle is not affected, and most cysts are incidental.




Inflammation of the Ovary: Oophoritis, or inflammation of the ovary, is rare in domestic animals. Infectious bovine rhinotracheitis virus (bovine herpesvirus 1 [BoHV-1]) viremia in experimental studies can induce necrotizing oophoritis in the postestrus cow. A cloudy fibrinous fluid fills some follicles. Microscopically, the lesions in the corpus luteum range from focal necrosis and the presence of mononuclear cells to diffuse hemorrhage and necrosis. Most affected ovaries also have necrotic follicles and mononuclear cells in the stroma. Bovine viral diarrhea (BVD) virus, a vertically and horizontally transmitted virus responsible for mild-to-fatal enteric disease and reproductive failure, can localize in bovine oocytes and cumulus cells and cause chronic oophoritis. Infection of ovarian oocytes with BVD virus is one of several possible routes of transmission of the virus from cow to fetus. Bacterial oophoritis occasionally is found in cats and dogs. In cats, it must be differentiated from feline infectious peritonitis (FIP). The inflammation is around the ovary and within the uterine tube, suggesting that the causative bacteria ascended from the uterus.



Miscellaneous Diseases of the Ovary: Supernumerary follicles occur in bovine ovaries when FSH is used in doses to cause superovulation in preparation for embryo transfer. There may be more than a dozen well-developed ovarian follicles or corpora lutea.


Adhesions between infundibulum and ovary vary from thin bands to large sheets of fibrous tissue binding the walls together. The lesion is often bilateral in cows and results from ascending infection after postpartum metritis. Physical trauma from rectal palpation and manipulation of the ovary is another possible cause; infundibular adhesions are common in beef heifers. Adhesions can obstruct or cause retention of fluids and result in a cystic infundibulum.


A small amount of hemorrhage is normal at the time of ovulation in all species. The mare is an exception because the follicles are large and the cavity of the ovulated follicle fills with blood to form a large corpus hemorrhagicum. In rare cases, the hemorrhage can be extensive enough to form an ovarian hematoma or even hemoperitoneum. If the hematoma extends through the ovulation fossa, the corpus luteum develops external to the ovarian capsule. In the mare and cow, a focal area of serositis is detectable at the point of ovulation. Progression through a fibrinous to a fibrous stage is rapid, and an “ovulation tag” is formed. The manual expression of a persistent corpus luteum in the cow sometimes results in severe periovarian hemorrhage. Organization of the hematoma results in adhesions between the ovary and adjacent structures, such as infundibulum of the uterine tube, and causes infertility. Excessive hemorrhage into follicles is sometimes present in calves, and hemorrhage into cystic follicles occurs occasionally in the bitch.


Atretic follicles are those that become arrested at any stage of development and then regress. In any estrous cycle, only one or a small number of follicles is destined to mature, whereas the others undergo atresia at various stages of maturation. A similar process occurs in seasonal anestrus and in all domestic species during pregnancy, except for the mare. Follicular atresia is considered abnormal when it is a part of any disease process that interferes with the release of or the pituitary response to GnRH. Development of the follicle can be arrested at any stage, and after an undetermined amount of time, it degenerates. The ovum undergoes apoptosis first; then the granulosa cells become pyknotic, vacuolated, and desquamate. The follicle either persists as a cyst with a partial thin lining of granulosa cells or is replaced by macrophages, theca cells, and fibrous connective tissue, eventually becoming a small scar.



Neoplasms: There are three main groups of primary ovarian neoplasms in domesticated animals: germ cell, sex cord stromal, and epithelial neoplasms. Little is known of ovarian carcinogenesis. Neoplasms rarely metastasize to the ovary of domestic mammals.



Germ cell neoplasms: Neoplasms arising from germ cells can differentiate along either embryonic or extraembryonic lines and are benign or malignant. The majority of neoplasms of germ cells are benign and undifferentiated (dysgerminoma) or benign with somatic differentiation (teratoma).


Dysgerminoma is a rare neoplasm of all species. It is usually a white solid friable lobulated mass with areas of hemorrhage and necrosis. It is composed of large round cells with a high nuclear to cytoplasmic ratio and many mitoses. This neoplasm is identical to seminoma in the testis. Metastases are rare.


Ovarian teratomas are rare and usually well differentiated and benign. They have disorganized elements of at least two of the three embryonic germ layers: ectoderm, including neuroepithelium; mesoderm; and endoderm. Skin with hair is often present (Fig. 18-13). Bone, cartilage, nervous tissue, fat, and respiratory epithelium are frequently seen. Malignant teratomas occur less often, and they are usually poorly differentiated with primitive tissue types.




Sex cord stromal neoplasms: Sex cord stromal neoplasms have a phenotype that resembles the tissues derived from the sex cords and/follicles. Most have regions with any combination of granulosa cell, theca cell, luteal cell, Sertoli cell, or interstitial endocrine cell phenotypes. Granulosa cell phenotype usually predominates, thus most are called granulosa cell tumors. Most produce estrogens, androgens, and/or inhibin. The mare can have signs of anestrus (inhibin-producing), nymphomania (estrogen-producing), or stallion-like behavior (androgen-producing); the bitch is likely to have prolonged estrus and may develop pyometra.



Granulosa cell tumors: Granulosa cell tumors are the most common ovarian neoplasms reported in large animals. They are unilateral, smooth surfaced, and round and can be 20 to 30 cm in diameter. They can be solid, cystic, or polycystic (Fig. 18-14, A and B). The cysts can vary from microscopic size to several centimeters in diameter. Often, the fluid within the cysts is red-brown. Microscopically, the neoplastic cells resemble normal granulosa cells and often are arranged as they would be in normal Graafian follicles: in single or multiple rows of round to columnar cells lining fluid-filled spaces (Fig. 18-14, C). In less differentiated areas, the neoplastic cells are arranged in sheets. Sometimes, especially in queens, Call-Exner bodies are present. These are rosettes of granulosa cells around a central space. The stroma can be sparse or plentiful. Granulosa cell tumors in the mare and cow are usually benign, are sometimes malignant in the bitch, and are often malignant in the queen; prognostic criteria are not well established.


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Sep 17, 2016 | Posted by in GENERAL | Comments Off on Female Reproductive System and Mammary Gland
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